title: Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy.
abstract: BACKGROUND
  There is a lack of new therapeutic strategies for IgA nephropathy. Low-dose sirolimus inhibits mesangial cell proliferation and renal fibrosis in animal models.
  
  
  METHODS
  We performed a pilot, randomized controlled trial to evaluate the efficacy and safety of low-dose sirolimus in patients with a high-risk IgA nephropathy. Twenty-three patients with a glomerular filtration rate (GFR) within 30-60 mL/min and/or proteinuria >1 g/day were randomly assigned to low-dose sirolimus plus enalapril and atorvastatin (SRL group, n = 14) or enalapril plus atorvastatin (CONTROL group, n = 9). Primary composite end point was variation of haematuria, proteinuria and blood pressure. Secondary end points were isotopic GFR, renal histology evaluated by Oxford classification and safety parameters evaluated at 6 and 12 months.
  
  
  RESULTS
  Primary end point improved significantly in the SRL group at 12 months. Regarding isotopic GFR, patients included in the CONTROL group lost 8 mL/min/1.73 m(2), whereas those in the SRL arm improved 5 mL/min/1.73 m(2) (P = 0.03). Proteinuria decreased similarly in both study groups. At 1 year, SRL treatment was associated with a significant reduction of mesangial and endocapillary proliferation, whereas glomerular sclerosis, tubular atrophy and interstitial fibrosis were similar. Sirolimus was well tolerated; all patients remained on therapy at 12 months.
  
  
  CONCLUSIONS
  The addition of low-dose sirolimus to enalapril and statin is safe, stabilizes renal function and reduces glomerular proliferative lesions in patients with poor prognosis IgA nephropathy.
authors.affiliation: Department of Nephrology, Hospital Universitari de Bellvitge, University of Barcelona, IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain. jmcruzado@bellvitgehospital.cat
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Rafael
authors.initials: R
authors.lastname: Poveda
authors.forename: Meritxell
authors.initials: M
authors.lastname: Ibernón
authors.forename: Montserrat
authors.initials: M
authors.lastname: Díaz
authors.forename: Xavier
authors.initials: X
authors.lastname: Fulladosa
authors.forename: Marta
authors.initials: M
authors.lastname: Carrera
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Itziar
authors.initials: I
authors.lastname: Navarro
authors.forename: José
authors.initials: J
authors.lastname: Ballarín
authors.forename: Ramón
authors.initials: R
authors.lastname: Romero
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA / Q000188:drug therapy*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D011758:Pyrroles / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D004656:Enalapril; D000069059:Atorvastatin; D020123:Sirolimus